Objective:

To elucidate the associations and causal pathways linking renal function, somatopsychic phenotypes, and dopaminergic metabolism with the incidence of restless legs syndrome (RLS) in maintenance hemodialysis patients.

Approach:

• Longitudinal Cohort Study: A matched 5-year longitudinal cohort study (N = 192) utilized multivariable generalized estimating equations (GEE) to assess risk factors for RLS.
• Mendelian Randomization: Bidirectional and network two-sample Mendelian randomization (MR) was conducted using independent GWAS statistics to explore causal relationships between renal impairment and dopamine metabolism.

Key Findings:

• Sarcopenia (Adjusted OR = 1.58, p = 0.002) and depressive severity (Adjusted OR = 1.10, p < 0.001) independently predicted 5-year incident RLS.
• Chronic trajectories of depression, anxiety, frailty, and sarcopenia mediated 44.4%, 45.5%, 45.8%, and 46.2% of the total risk pathways for RLS, respectively (all p < 0.001).
• Lower eGFR was causally associated with increased depression risk (IVW: β = −0.579, p = 0.004), which mediated a substantial indirect effect on suppressed dopamine metabolism.

Interpretation:

The study establishes a cascade where chronic phenotypic deterioration and genetically predicted depression mediate the pathway from renal impairment to suppressed dopamine metabolism.

Limitations:

• The study relies on observational data, which may be subject to residual confounding.
• The generalizability of findings may be limited to specific populations undergoing maintenance hemodialysis.

Conclusion:

This research highlights multi-system targets for early RLS screening.